Sudheer Arava

Causes of pulmonary granulomas: a retrospective study of 500 cases from seven countries

Background The frequencies of various causes of pulmonary granulomas in pathological material are unknown, as is the influence of geographical location on aetiology. The aim of this study was to identify the causes of pulmonary granulomas in pathological specimens, to define their frequencies, and to determine whether these causes vary by geographical location. Methods 500 lung biopsies and resections containing granulomas were reviewed retrospectively by expert pulmonary pathologists from 10 institutions in seven countries. Fifty consecutive cases from each location were assigned a diagnosis based on histological features and available clinical/microbiological data. Results A specific cause was identified in 58% of cases (290/500), most commonly sarcoidosis (136, 27%) and mycobacterial or fungal infections (125, 25%). Mycobacteria were identified in 19% of cases outside the USA versus 8% within the USA. In contrast, fungi accounted for 19% cases in the USA versus 4% in other locations. Fungi were mostly detected by histology, whereas most mycobacteria were identified in cultures. In 42% of cases (210/500) an aetiology could not be determined. Conclusions Across several geographical settings, sarcoidosis and infections are the most common causes of pulmonary granulomas diagnosed in pathological specimens. Fungi are more commonly identified than mycobacteria in the USA, whereas the reverse is true in other countries. A definite aetiology cannot be demonstrated in more than a third of all cases of pulmonary granulomas, even after histological examination. These findings highlight the need to submit material for histology as well as cultures in all cases in which granulomatous disease enters the differential diagnosis.

Role of p40 and cytokeratin 5/6 in the differential diagnosis of sinonasal undifferentiated carcinoma

Sinonasal undifferentiated carcinoma (SNUC) is an epithelial neoplasm of sinonasal region which does not exhibit a squamous or glandular differentiation. The challenge in diagnosis of this entity is the rarity of the disease, the varying morphology of the tumor which leads to gamut of differential diagnosis and the paucity of consistent immunohistochemical markers except pancytokeratin. Forty-one cases of sinonasal epithelial neoplasm consisting of 11 cases of SNUC and 10 cases each of high-grade (grade 3 and 4) esthesioneuroblastoma, undifferentiated nasopharyngeal carcinoma, and poorly differentiated squamous cell carcinoma of the sinonasal region were analyzed for morphology and immunoexpression of CK5/6 and p40. It was found that SNUC did not exhibit immunohistochemical expression of p40 and CK 5/6, suggesting that these could be useful negative immune markers for diagnosis of SNUC.

Anterior Mediastinal Mass: A Rare Presentation of Tuberculosis

We report a case of a 14-year-boy who presented to us with a low-grade fever with evening rise for 9 months. Along with this, the patient also reported a reduction in his appetite and body weight. He had a mild dry cough but no respiratory symptoms otherwise. There was no other localization for fever on history. He received antitubercular therapy, based on abnormal chest radiograph. However, there was no relief in his symptoms. General physical examination revealed mild fever. Systemic examination was unremarkable. Blood investigations done for fever were noncontributory. Computed tomographic (CT) scan of the chest revealed a mediastinal mass compressing the trachea. The possibilities of lymphoma or germ cell tumour were considered. A biopsy from the mass under CT guidance was performed. The histopathology revealed multiple epithelioid cell granulomas with necrosis, and the diagnosis of tuberculosis was made. The clinical course of this patient and the relevant literature is presented in this paper.

Beneficial effects of aqueous extract of stem bark of Terminalia arjuna (Roxb.), An ayurvedic drug in experimental pulmonary hypertension.

ETHNOPHARMACOLOGICAL RELEVANCE The stem bark of Terminalia arjuna (Roxb.) is widely used in Ayurveda in various cardiovascular diseases. Many animal and clinical studies have validated its anti-ischemic, antihypertensive, antihypertrophic and antioxidant effects. Pulmonary hypertension (PH) is a fatal disease which causes right ventricular hypertrophy and right heart failure. Pulmonary vascular smooth muscle hypertrophy and increased oxidative stress are major pathological features of PH. As available limited therapeutic options fail to reduce the mortality associated with PH, alternative areas of therapy are worth exploring for potential drugs, which might be beneficial in PH. AIM OF THE STUDY The effect of a standardised aqueous extract of the stem bark of Terminalia arjuna (Roxb.) in preventing monocrotaline (MCT)-induced PH in rat was investigated. MATERIALS AND METHODS The study was approved by Institutional Animal Ethics Committe. Male Wistar rats (150-200g) were randomly distributed into five groups; Control, MCT (50mg/kg subcutaneously once), sildenafil (175µg/kg/day three days after MCT for 25 days), and Arjuna extract (TA125 and TA250 mg/kg/day orally after MCT for 25 days). PH was confirmed by right ventricular weight to left ventricular plus septum weight (Fulton index), right ventricular systolic pressure (RVSP), echocardiography, percentage medial wall thickness of pulmonary arteries (%MWT). Oxidative stress in lung was assessed by super oxide dismutase (SOD), catalase, reduced glutathione (GSH) and thiobarbituric acid reactive substance (TBARS). The protein expressions of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX-1) in lung and gene expression of Bcl2 and Bax in heart were analyzed by Western blot and RT PCR respectively. RESULTS MCT caused right ventricular hypertrophy (0.58±0.05 vs 0.31±0.05; P<0.001 vs. control) and increase in RVSP (33.5±1.5 vs 22.3±4.7mm of Hg; P<0.001). Both sildenafil and Arjuna prevented hypertrophy and RVSP. Pulmonary artery acceleration time to ejection time ratio in echocardiography was decreased in PH rats (0.49±0.05 vs 0.32±0.06; P<0.001) which was prevented by sildenafil (0.44±0.06; P<0.01) and TA250 (0.45±0.06; P<0.01). % MWT of pulmonary arteries was increased in PH and was prevented by TA250. Increase in TBARS (132.7±18.4 vs 18.8±1.6nmol/mg protein; P<0.001) and decrease in SOD (58.4±14.1 vs 117.4±26.9U/mg protein; P<0.001) and catalase (0.30±0.05 vs 0.75±0.31U/mg protein; P<0.001) were observed in lung tissue of PH rats, which were prevented by sildenafil and both the doses of Arjuna extract. Protein expression of NOX1 was significantly increased in lung and gene expression of Bcl2/Bax ratio was significantly decreased in right ventricle in MCT-induced PH, both were significantly prevented by Arjuna and sildenafil. CONCLUSIONS Aqueous extract of Terminalia arjuna prevented MCT-induced pulmonary hypertension which may be attributed to its antioxidant as well as its effects on pulmonary arteriolar wall thickening.

Febuxostat ameliorates doxorubicin-induced cardiotoxicity in rats

The clinical use of doxorubicin is associated with dose limiting cardiotoxicity. This is a manifestation of free radical production triggered by doxorubicin. Therefore, we evaluated the efficacy of febuxostat, a xanthine oxidase inhibitor and antioxidant, in blocking cardiotoxicity associated with doxorubicin in rats. Male albino Wistar rats were divided into four groups: control (normal saline 2.5mL/kg/dayi.p. on alternate days, a total of 6 doses); Doxorubicin (2.5mg/kg/dayi.p. on alternate days, a total of 6 doses), Doxorubicin+Febuxostat (10mg/kg/day oral) and Doxorubicin+Carvedilol (30mg/kg/day oral) for 14days. Febuxostat significantly ameliorated the doxorubicin-induced deranged cardiac functions as there was significant improvement in arterial pressures, left ventricular end diastolic pressure and inotropic and lusitropic states of the myocardium. These changes were well substantiated with biochemical findings, wherein febuxostat prevented the depletion of non-protein sulfhydryls level, with increased manganese superoxide dismutase level and reduced cardiac injury markers (creatine kinase-MB and B-type natriuretic peptide levels) and thiobarbituric acid reactive substances level. Febuxostat also exhibited significant anti-inflammatory (decreased expression of NF-κBp65, IKK-β and TNF-α) and anti-apoptotic effect (increased Bcl-2 expression and decreased Bax and caspase-3 expression and TUNEL positivity). Hematoxylin and Eosin, Masson Trichome, Picro Sirius Red and ultrastructural studies further corroborated with hemodynamic and biochemical findings showing that febuxostat mitigated doxorubicin-induced increases in inflammatory cells, edema, collagen deposition, interstitial fibrosis, perivascular fibrosis and mitochondrial damage and better preservation of myocardial architecture. In addition, all these changes were comparable to those produced by carvedilol. Thus, our results suggest that the antioxidant and anti-apoptotic effect of febuxostat contributes to its protective effects against doxorubicin-induced cardiotoxicity.

Intralesional radiofrequency ablation for nodular angiolymphoid hyperplasia on forehead: a minimally invasive approach.

Angiolymphoid hyperplasia with eosinophilia (ALHE) is an idiopathic acquired condition characterized by erythematous papulo-nodular lesions with a predilection for the head and neck. The lesions are cosmetically disfiguring, resistant to most medical and surgical therapies and tend to recur. We report the novel use of radiofrequency equipment in the management of nodular ALHE on forehead of a 53-year-old man. Intra-lesional radiofrequency ablation was done using a modified 18 gauge intravenous cannula and three sittings over a period of four years yielded cosmetically acceptable results with no recurrence and minimal side effects.

Conventional Transbronchial Needle Aspiration Versus Endobronchial Ultrasound–guided Transbronchial Needle Aspiration, With or Without Rapid On-Site Evaluation, for the Diagnosis of Sarcoidosis: A Randomized Controlled Trial

Background: Endobronchial ultrasound–guided transbronchial needle aspiration (EBUS-TBNA) as a standalone modality is superior to conventional TBNA (c-TBNA) for the diagnosis of sarcoidosis. However, the overall yield is not different if combined with endobronchial biopsy (EBB) and transbronchial lung biopsy (TBLB). The utility of rapid on-site evaluation (ROSE) in a comparative evaluation of EBUS-TBNA versus c-TBNA for the diagnosis of sarcoidosis has not been previously evaluated. Methods: Eighty patients with suspected sarcoidosis were randomized 1:1:1:1 into 4 groups: c-TBNA without ROSE (TBNA-NR), c-TBNA with ROSE (TBNA-R), EBUS-TBNA without ROSE (EBUS-NR), and EBUS-TBNA with ROSE (EBUS-R). EBB and TBLB were performed in all patients. Primary objective was detection of granulomas for combined procedure. Secondary objectives were individual procedure yields, sedation dose, and procedure duration. Patients without a diagnosis following c-TBNA subsequently underwent EBUS-TBNA. Results: A total of 74 patients were finally diagnosed with sarcoidosis. Overall, granuloma detection was not significantly different between the 4 groups (68% in TBNA-NR, 89% in TBNA-R, 84% in EBUS-NR, and 83% in EBUS-R groups, P=0.49). The yield of c-TBNA in the TBNA-NR group was lower compared with that in TBNA-R group and EBUS-TBNA in EBUS groups (32%, 72%, 68%, and 67% for TBNA-NR, TBNA-R, EBUS-NR, and EBUS-R groups, respectively, P=0.04). Additional 20% patients were diagnosed when EBUS-TBNA was performed following a nondiagnostic bronchoscopy procedure in the TBNA-NR group. Sedation requirement and procedure duration were significantly lower with c-TBNA as compared with EBUS-TBNA (P<0.001). Conclusion: When performing TBNA in the setting of suspected sarcoidosis, we found c-TBNA with ROSE and EBUS-TBNA (with or without ROSE) to be superior to c-TBNA alone. Whether c-TBNA with ROSE is equivalent to EBUS-TBNA cannot be determined from our study due to small sample size/low power.

Utility of semi‑rigid thoracoscopy in undiagnosed exudative pleural effusion

Background: Semi-rigid thoracoscopy is a safe and efficacious procedure in patients with undiagnosed pleural effusion. Literature on its utility from developing countries is limited. We herein describe our initial experience on the utility of semi-rigid thoracoscopy from a tertiary care teaching and referral center in north India. We also perform a systematic review of studies reporting the utility of semi-rigid thoracoscopy from India. Patients and Methods: The primary objective was to evaluate the diagnostic utility of semi-rigid thoracoscopy in patients with undiagnosed exudative pleural effusion. Semi-rigid thoracoscopy was performed under local anesthesia and conscious sedation in the bronchoscopy suite. Results: A total of 48 patients underwent semi-rigid thoracoscopy between August 2012 and December 2013 for undiagnosed pleural effusion. Mean age was 50.9 ± 14.1 years (range: 17-78 years). Pre-procedure clinico-radiological diagnoses were malignant pleural effusion [36 patients (75%)], tuberculosis (TB) [10 (20.83%) patients], and empyema [2 patients (4.17%)]. Patients with empyema underwent the procedure for pleural biopsy, optimal placement of intercostal tube and adhesiolysis. Thoracoscopic pleural biopsy diagnosed pleural malignancy in 30 (62.5%) patients and TB in 2 (4.17%) patients. Fourteen (29.17%) patients were diagnosed with non-specific pleuritis and normal pleura was diagnosed on a pleural biopsy in 2 (4.17%) patients. Overall, a definitive diagnosis of either pleural malignancy or TB was obtained in 32 (66.7%) patients. Combined overall sensitivity, specificity, positive predictive value and negative predictive value of thoracoscopic pleural biopsy for malignant pleural effusion were 96.77%, 100%, 100% and 66.67%, respectively. There was no procedure-related mortality. On performing a systematic review of literature, four studies on semi-rigid thoracoscopy from India were identified. Conclusion: Semi-rigid thoracoscopy is a safe and efficacious procedure in patients with undiagnosed exudative pleural effusions.

Cerebral aspergillus infection in pediatric acute lymphoblastic leukemia induction therapy.

Angioinvasive pulmonary infection from filamentous fungi is not an uncommon occurrence in immunocompromised patients like acute lymphoblastic leukemia (ALL). Rarely, these lesions can spread via the hematogenous route and involve multiple visceral organs. We report a case of a 14-year-old boy with ALL who developed angioinvasive pulmonary aspergillosis early in the course of induction therapy, which was followed by hematogenous dissemination and formation of multiple brain abscesses. The patient was treated with intravenous amphotericin B. There was no response to the therapy and the patient succumbed to disseminated infection. Postmortem lung biopsy confirmed angioinvasive pulmonary aspergillosis. Poor penetration of amphotericin B across the blood-brain barrier could be one of the contributory factors for poor response to antifungal therapy. We discuss the various antifungal agents with respect to their penetration in brain.

Cytological diagnosis of peritoneal endometriosis

Sir, Endometriosis is a common disease characterized by ectopic growth of endometrial tissue that responds to hormonal stimulation. It primarily affects women in the reproductive age group with mixed symptomatology. Cytological features of endometrial cells in peritoneal fluid are not well described, which we wish to highlight. A 30-year-old woman presented with lower abdominal pain and dysmenorrhoea of 1 year duration. On examination, she had mild ascites. Bilateral cysts were seen near the fallopian tube on laparoscopy. Diagnostic considerations included neoplastic process or pelvic endometriosis. A peritoneal wash was performed and 100 mL of haemorrhagic fluid was sent for cytological examination. On microscopy, the fluid showed the presence of endometrial cells. The glandular epithelial cells were arranged in variably sized spheres in which the periphery showed epithelial cells, along the border and as a honeycombed sheet, with a cluster of stromal cells in the centre having hyperchromatic nuclei, scant cytoplasm and indistinct cytoplasmic borders [Figure 1]. There was no nuclear atypia and the nucleoli were inconspicuous. Some of the fragments were arranged in a small ball-like configuration in which there was cytoplasm resembling mesothelial cells [Figure 2]. Their three-dimensional nature and tight grouping set them apart from the loose sheets of mesothelial cells of the peritoneal wash. A few hemosiderin-laden macrophages were identified. A cytological diagnosis of endometriosis was made. Figure 1 Large endometrial fragment in peritoneal wash fluid showing epithelial lining on the outside, seen on the sides and as honeycombed cells as well as compact stromal cells within (PAP, ×400) Figure 2 Small spherule of endometrial cells in three-dimensional arrangement, which has to be differentiated from reactive mesothelial cells (PAP, ×400) The utility of peritoneal wash cytology for diagnosis of endometriosis has been reported.[1,2] In most cases, only hemosiderin-laden macrophages are identified.[2–5] The presence of endometrial cells is more specific but less sensitive than hemosiderin-laden macrophages for the diagnosis of endometriosis. The endometrial cells have been reported in 25%–52% of peritoneal washes done in endometriosis.[1,5] However, recognition of endometrial cells as well as hemosiderin-laden macrophages is essential for diagnosis on morphological basis alone.[6,7] The descriptions, diagnostic features and illustration of endometrial cell morphology in the peritoneal wash fluid is restricted to a few reports.[3,6] The distinction of endometrial cells from mesothelial cells and adenocarcinoma cells is important. Endometrial cells come in three-dimensional fragments that do not resemble mesothelial cells architecturally in washings which are arranged in sheets. However, endometriosis may elicit reactive mesothelial proliferation, which form three-dimensional fragments with calcific concretions, which are difficult to distinguish from endometrial cells.[5] Larger endometrial cell fragments may include stromal cells, which is a useful feature for differentiation as seen in the present case. Presence of hemosiderin-laden macrophages is indirect evidence of endometriosis. In the presence of an adnexal mass, a well-differentiated adenocarcinoma is always a diagnostic consideration and needs to be ruled out by the absence of atypia in the small cells and nuclei of endometrial cells. This distinction becomes difficult if there is reactive mesothelial proliferation in case of endometriosis.[2,5] The use of cell blocks and immunocytochemistry for epithelial and mesothelial cell markers can greatly aid diagnosis in distinction between reactive mesothelial fragments on one side and endometriosis and adenocarcinoma on the other.[2] Correlation with clinical and operative features is essential before cytological diagnosis.